HIV-associated nephropathy has emerged as the third leading cause of ESRD in African Americans in the United States. This dramatic change has occurred within the past 8 years moving from an entity whose existence was often debated, to a disease affecting over 100 patients per year. The financial and personal costs are well known to physicians in high HIV prevalence communities and where Blacks account for significant percentage of the AIDS patients. Despite these dramatic demographic changes in the HIVAN epidemic, a great deal still needs to be learned about the pathogenesis of this disease if we are able to adopt appropriate treatment and prevention strategies. Significant progress has been made to address this disease. We now know that HIV-1 is directly involved in the disease process: viral genes expressed in an animal model are capable of reproducing all features of HIVAN in man, renal epithelial cells appear to be a major target for HIV pathogenesis, and recent data suggest viral entry into renal epithelial cells is likely. In this PPG, we intend to explore the pathogenesis of HIVAN by focusing on three key questions: 1. What is the genetic basis for racial predilection for HIVAN? 2. What are the viral factors responsible for pathogenesis, and 3. What is the relationship between HIV-1 and the host response that leads to the development of HIVAN? Using both the transgenic mouse model developed and extensively characterized in our laboratory as well as human specimens, we will address these questions. Project #1 will identify candidate genes by positional cloning methods that may be responsible for enhancing the severity of HIVAN or its phenotypic penetrance. Project #2 will explore mechanisms of viral pathogenesis including the evolution of renal quasispecies, the mechanisms of viral entry, and the steps in the viral life cycle supported by the renal epithelia. Project #3 will explore viral-host interactions by determining which viral gene product(s) are responsible for initiating HIVAN and the host response to infection using representational difference analysis to identify candidate pathways. The cores provide essential support functions. Core A will provide the administrative support for the PPG. Core B will provide animal breeding support and pathological assessment of renal disease as well as a central repository for human samples and clinical database for HIV-1 infected patients with renal disease. The repository will include renal biopsy and primary viral isolates.